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El cáncer de mama operable: modelo de investigacion traslacional
Dr Ramon Colomer
Hospital Universitario La Princesa
Preclínica Fase 1 Fase 2 Fase 3 Fase 4
Fases de los Ensayos Clínicos
Mediados de los años 60
FDA EMEA
Preclinico Fase 1 Fase 2 Fase 3 Fase 4
Fases de los Ensayos Clínicos
FDA EMEA
Preclínica Fase 1 Fase 2 Fase 3 Fase 4
Fases de los Ensayos Clínicos
Fase 0 x Respuestas moleculares
Clin Cancer Res; 19(23) December 1, 2013
Newly diagnosed, untreated patients with ER+ localized breast cancer likely to benefit from hormonal therapy
Palpable tumor: > 2 cm diameter
Tumor biopsies (surgery)
RANDOMIZE
Letrozole 2.5 mg/day Everolimus 10 mg/day
Letrozole 2.5 mg/day Placebo
n = 138
16 weeks
Surgery
Tumor biopsies (pretreatment)
Tumor biopsies (2 weeks)
SCREEN
n = 132
Baselga et al. J Clin Oncol. 2009 Jun 1;27(16):2630-7
Phase 2 Neoadjuvant letrozole
everolimus
a variety of markers, including phosphorylated S6 protein at Ser235, phosphorylated S6 protein at Ser240, cyclin D1, progesterone, and Ki67. Sequencing of PIK3CA exons 9 and 20 and of TP53 exons 5 to 8 was performed
Phase 2 (Study 2222): Neoadjuvant letrozole
everolimus
• 270 postmenopausal women received 4 months of letrozole 2.5 mg qd plus everolimus 10 mg qd or placebo as neoadjuvant therapy
• Reductions in Ki67 (a cellular marker for proliferation) expression occurred in 57% of everolimus patients and in 30% of the control patients
• Biomarker analysis will determine whether a patient population with a greater likelihood of responding can be identified
Response Rates (CR+PR)
Assessment
Everolimus + Letrozole n = 138
Placebo + Letrozole n = 132 P
Palpation 68.1% 59.1% 0.062*
Ultrasound 58.0 % 47.0 % 0.035*
*1-sided level of significance of 10%
Baselga et al. J Clin Oncol. 2009 Jun 1;27(16):2630-7
Effects of PIK3CA mutation status on antiproliferative response to therapy
• Patients with PIK3CA exon 9 mutations were less responsive to letrozole alone but as sensitive as the overall population to everolimus + letrozole
70
60
50
40
30
20
10
0
PIK3CA e9 mutant only
PIK3CA e20 mutant only
PIK3CA wt only
n≥8 in all subsets
Percentage of cases with Ki67 ≤2 at Day 15
0
-20
-40
-60
-100
-80
-120 Everolimus + letrozole
Letrozole
PIK3CA e9 mutant only
PIK3CA e20 mutant only
PIK3CA wt only
Percentage reduction in Ki67 from baseline at Day 15
Baselga et al. J Clin Oncol 2009;27:2630–7.
Representative examples of 18F-FDG PET/CT metabolic responder and nonresponder
Baseline week 2 week 6
Phase II randomized BYL719 or buparlisib, for the neoadjuvant treatment of postmenopausal women with HR+HER2-breast cancer
BYL719A2201
Sequence of I-SPY 2 trial
26
Allocation: randomized
Intervention model: Parallel assignment
Masking: Open label
Estimated enrollment : 800 patients
Multicentrique
Informations about the study
I-SPY 2 STUDY
Agent Company Agent Category Delivery
ABT-888 Abbott Poly(ADP-Ribose) Polymerase (PARP) Inhibitor
Oral
Figitumumab (CP-751,871)
Pfizer Insulin-like Growth Factor Type1 Receptor (IGF-1R) Antagonist,
IV
Neratinib (HKI-722)
Wyeth, Pfizer, Puma
Multikinase Inhibitor; EGFR, HER2, HER3 Inhibitor
Oral
Conatumumab (AMG 655)
Amgen Apoptosis Inducer, TRAIL Receptor Agonist
IV
AMG 386 Amgen Angiogenesis Inhibitor, Angiopoietin 1 and 2-Neutralizing Fusion Protein
IV
MK-2206 Merck Allosteric Akt inhibitor Oral
T-DM1 Roche Trastuzumab with emtansine Iv
Pertuzumab Roche antiHER2 antibody iv
27
I-SPY 2 STUDY
Agents selected
Agent Company Agent Category Delivery
ABT-888 Abbott Poly(ADP-Ribose) Polymerase (PARP) Inhibitor
Oral
Figitumumab (CP-751,871)
Pfizer Insulin-like Growth Factor Type1 Receptor (IGF-1R) Antagonist,
IV
Neratinib (HKI-722)
Puma Multikinase Inhibitor; EGFR, HER2, HER3 Inhibitor
Oral
Conatumumab (AMG 655)
Amgen Apoptosis Inducer, TRAIL Receptor Agonist
IV
AMG 386 Amgen Angiogenesis Inhibitor, Angiopoietin 1 and 2-Neutralizing Fusion Protein
IV
MK-2206 Merck Allosteric Akt inhibitor Oral
T-DM1 Roche Trastuzumab with emtansine Iv
Pertuzumab Roche antiHER2 antibody iv
28
I-SPY 2 STUDY
Agents selected
Tryphaena study design
HER2-positive
EBC
centrally confirmed
(N = 225)
FEC
Trastuzumab
to complete
1 year
S
u
r
g
e
r
y
Docetaxel
Cycles 1‒3 4‒6
Pertuzumab + trastuzumab
Pertuzumab + trastuzumab
FEC Docetaxel
Carboplatin
Docetaxel
Pertuzumab + trastuzumab C
B
A
Day –28
Tumour tissue
assessment for
HER2-positivity and
subsequent assessment
for other biomarkers
following randomisation
Day –14
Serum and
blood samples
collected
At surgery
Serum and tissue samples collected
(N.B. tumour tissue samples were only
available in patients with residual disease)
Biomarker analysis
Method qRT-PCR IHC FISH ELISA Mutational
analyses
PCR-based
polymorphism
analyses
Biomarkers
assessed
HER2
HER3
EGFR
Amphiregulin
Betacellulin
HER2
HER3
IGF-1R
PTEN
c-Myc
TOP2A
sHER2
Amphiregulin
TGFα
EGF
PI3K
(8 mutations)
Fcγ-receptor
polymorphisms
EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor;
IGF-1R, insulin-like growth factor 1 receptor; IHC, immunohistochemistry; PI3K, phosphoinositide-3-kinase; PTEN, phosphatase and tensin
homologue; sHER2, shed HER2; TGFα, transforming growth factor alpha; TOP2A, topoisomerase 2 alpha
• The biomarker analysis population was a subset of the intention-to-treat population, and
included all patients who had valid biomarker data
• All IHC data are shown as H-scores
– For each biomarker a modified H-score was derived by classifying the intensity of
staining according to three categories (1+, 2+, 3+) and assessing the percentage of
tumour cells within each staining intensity (P1, P2, P3, respectively)
• Modified H-score = (1+1)
P1 + (2+1)
P2 + (3+1)
P3
– This score has a maximum value of 400
0 20% 40% 60% 80% 100%
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
No Yes
HER2 Mem H-Score
pCR Rate (95% CI)
Arm A Biomarker Arm B Arm C
HER3 Mem H-Score
IGF-1R Mem H-Score
EGFR Mem H-Score
PTEN Cyt H-Score
PTEN Nuc H-Score
EGFR-CR (qRT-PCR)
HER2-CR (qRT-PCR)
HER3-CR (qRT-PCR)
Amphiregulin-CR (qRT-PCR)
HER2/HER3-CR (qRT-PCR)
TOP2A Ratio Target/Cen.
C-Myc Ratio Target/Cen.
Serum Amphiregulin [pg/mL]
Serum EGF [pg/mL]
Serum sHER2 [ng/mL]
Serum TGF-alpha [pg/mL]
PIK3CA any mutation
0 20% 40% 60% 80% 100% High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
No Yes
0 20% 40% 60% 80% 100%
0 20% 40% 60% 80% 100% 0 20% 40% 60% 80% 100% 0 20% 40% 60% 80% 100%
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
High Low
No Yes
All biomarkers assessed by IHC are represented by H-scores; ---- Dashed lines indicate pCR rate irrespective of biomarker expression level
EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor;
IGF-1R, insulin-like growth factor 1 receptor; PIK3CA, phosphoinositide-3-kinase, catalytic, alpha polypeptide; PTEN, phosphatase and
tensin homologue; sHER2, shed HER2; TOP2A, topoisomerase 2 alpha
Relationship between biomarkers and pCR by treatment arm
Background
NeoSphere: Study design and main
results
Gianni L, et al. Lancet Oncol 2011 DOI:10.1016/S1470-2045(11)70336-9
S
U
R
G
E
R
Y
Study dosing: q3w x 4
THP (n=107) docetaxel (75 100 mg/m2) trastuzumab (8 6 mg/kg) pertuzumab (840 420 mg)
HP (n=107) trastuzumab (8 6 mg/kg) pertuzumab (840 420 mg)
TP (n=96) docetaxel (75 100 mg/m2) pertuzumab (840 420 mg)
TH (n=107) docetaxel (75 100 mg/m2) trastuzumab (8 6 mg/kg)
TH THP HP TP
50
40
30
20
10
0
pC
R, %
9
5%
CI
29
46
17
24
0
10
20
30
40
50
60
70
TH THP HP TP
ER or PR positive ER and PR negative
20 26
17
37
29 30
63
6
pC
R, %
9
5%
CI
Methods
Gene Expression Profiles from Neosphere
• Tumor samples were collected at diagnosis from 98% of the 407 patients enrolled in the Neosphere study (Gianni L et al, SABCS 2011)
• mRNA was extracted from formalin-fixed paraffin-embedded core biopsies in 387 cases (93% of all patients).
• Gene expression profiles (Affymetrix U133 Plus 2.0) were obtained for 367 samples (88% of all patients; 95% successful hybridization)
– TH (Docetaxel/Trastuzumab), n=90
– THP (Docetaxel/Trastuzumab/Pertuzumab), n=95
– HP (Trastuzumab/Pertuzumab), n=98
– TP (Docetaxel/Pertuzumab), n=84
Background for genes/metagenes selection
Mechanisms of action of trastuzumab and pertuzumab
1. Blockade/modulation of HER2 signaling
2. Antibody-Dependent Cellular Cytotoxicity and other immune mediated effects
Background for genes/metagenes selection
Mechanisms of action of trastuzumab and pertuzumab
1. Blockade/modulation of HER2 signaling
2. Antibody-Dependent Cellular Cytotoxicity and other immune mediated effects
A Pharmacokinetic-Pharmacodynamic Study of Enzastaurin in Localized, Invasive, Breast Carcinoma LB-256
Antonio Llombart Cussac, Xavier Matias-Guiu, Diego Marquez Medina, Sonia del Barco Berron, Edelmiro Iglesias Martinez, Jagatheswari Virayah, Gopi Ganji, Mark Phong, Taron Faelker, Eva Carrasco, Oluwatoyin Shonukan, Scott P Myrand, Luna Musib, Brian P Mullaney, Ramon Colomer
Enzastaurin is an orally administered inhibitor of the protein kinase C (PKC) and phosphatidylinositol 3-PI3K)/AKT pathways
Neoadjuvant paclitaxel ± Nintedanib with Proteomic and Dynamic Imaging Correlates
NCT01484080
44-002 pre
44-002 post
Desaparición hipoxia 15 días BIBF – respuesta completa patológica Miller Payne
PRE Post
Hipoxia igual tras BIBF – ausencia total de respuesta
Proteómica pre- post- BIBF – Pool de 10 casos
Tumor congel
ado
Diseccion
areas >90%
Lisis y separacion peptidos
y fosfopépti
dos
Mediante TiO2
Espectrometria de masas
(Orbitrap)
Analisis con
Perseus (secuencia
s consenso)
Genome-forward neoadjuvant endocrine therapy trial design
Ellis MJ. Clin Cancer Res; 19(23) December 1, 2013
Biomarker stratified clinical trial design for evaluating novel targeted therapy in TNBC
Clin Cancer Res; 19(23) December 1, 2013
Repercusiones
• Mayor demanda en el Diagnóstico
Repercusiones
• Mayor demanda en el Diagnóstico
• Estudios en neoadyuvancia más frecuentes
Repercusiones
• Mayor demanda en el Diagnóstico
• Estudios en neoadyuvancia más frecuentes
• Tratamiento cada vez más personalizado
El cáncer de mama operable: modelo de investigacion traslacional
Dr Ramon Colomer
Hospital Universitario La Princesa
Clin Cancer Res; 19(23) December 1, 2013
Trial schema for FOCUS4
-1,5
-1
-0,5
0
0,5
1
1,5
Substratos de AMPK (Log10)
V0
V15
BIBF15